Abstract PD17-02: ctDNA Molecular Response based on breast cancer driver mutations predicts progression in aromatase inhibitor-sensitive first line treatment of oestrogen receptor-positive (ER+) HER2-negative (HER2-) advanced breast cancer
Authors: Caroline Bailleux, Thomas Bachelot, Francois-Clement Bidard, Anne-Claire Hardy-Bessard, Ivan Bièche, Anne Pradines, Florian Clatot, thibault DE LA MOTTE ROUGE, Jean-Luc Canon, Barbara Pistilli, Kyle Chang, Katie J. Quinn, Heather L. Gustafson, Florence Dalenc, Cyril Foa, Hanifa Ammarguellat, Chantal Bernard-Marty, Brigitte Lucas, Sophie Barthier, Fabrice Lorchel, Olivier Gisserot, Laurent Arnould, Marjorie Mauduit, Jérôme Lemonnier, Frédérique Berger, Suzette Delaloge, Fabrice Andre
Journal: Cancer Research (2023)

Abstract Background: The combination of a CDK4/6 inhibitor and an aromatase inhibitor (AI) is the gold standard for AI-sensitive first line treatment of ER+ HER2- advanced breast cancer. Nevertheless, some patients progress rapidly and may benefit from alternative strategies. Early ctDNA dynamics have been shown to predict disease course in several clinical situations. Here, we use samples from the PADA-1 trial to assess this strategy for patients receiving AI and palbociclib as first line treatment. PADA-1 was designed to assess the clinical utility of sequential analysis of ctDNA for emerging ESR1 mutations to trigger an early switch from AI plus palbociclib to fulvestrant plus palbociclib treatment. The study included 1,017 patients and was positive on its primary end-point. The objective of this translational study was to analyze the predictive value of 4-week molecular response (MR) for patient progression. Material &amp; Method: First, a CLIA-validated targeted next-generation sequencing-based test (Guardant360 Response) was used to characterize changes in ctDNA level via detection of somatic single-nucleotide variants (SNVs), insertion/deletion mutations (indels), and gene fusions in 74 genes frequently mutated in cancer. A second analysis was restricted to cancer-associated mutations in 11 genes commonly mutated in breast cancer (PIK3CA, GATA3, TP53, AKT1, ERBB2, BRCA1, BRCA2, ATM, ESR1, PALB2 and RB1). The threshold for molecular response was defined as ≥ 50% decrease in ctDNA (MR score &amp;lt; 0.5). Subjects with ctDNA levels below the test’s limit of quantitation (ctDNA-low) were considered molecular responders. Results: 372 subjects with matched baseline and 4-weeks samples were available for analysis. Of these, 134 subjects (36%) were ctDNA-low, and 238 subjects (64%) quantifiable. Among the quantifiable subjects, 183 (77%) were molecular responders (MR+, MR &amp;lt; 0.5), and 55 (23%) were not (MR–, MR ≥ 0.5). PFS was moderately improved for both MR+ and ctDNA-low relative to MR– (HR=0.61 (95%CI 0.44-0.85), p&amp;lt; 0.01) over the full 29 months of follow up. Differential PFS event rate was observed only in the first 8 months following ctDNA assessment; during this time MR+ and ctDNA-low were associated with more significantly decreased risk of progression (HR 0.24, 95% CI 0.13 – 0.43, p=0.0001). Limiting ctDNA assessment to genes commonly mutated in breast cancer enhanced the predictive power of MR (HR=0.08, 95% CI 0.04 0.17, p&amp;lt; 0.001, for MR+ and ctDNA-low vs. MR– across 8 months post-assessment); however, fewer samples were quantifiable by this method (169 [45%] quantifiable; 203 [55%] ctDNA-low). Combining MR status with additional molecular features (e.g.tumor mutational burden and maximum mutation allele fraction) did not improve prediction of non-response. Conclusion: Changes in ctDNA fraction during the first weeks of treatment are predictive of long term clinical benefit on an individual patient basis, particularly during the first year of therapy. Adjusting the MR threshold and/or limiting to genes known to be relevant in the specific tumor can tailor the assessment of ctDNA change to specific clinical scenarios where greater sensitivity or specificity may be required. The identification of patients at high risk for early clinical failure at the onset of treatment may allow for therapy escalation and/or change to improve outcome in this population. Funding: Pfizer and Guardant Health Citation Format: Caroline Bailleux, Thomas Bachelot, Francois-Clement Bidard, Anne-Claire Hardy-Bessard, Ivan Bièche, Anne Pradines, Florian Clatot, thibault DE LA MOTTE ROUGE, Jean-Luc Canon, Barbara Pistilli, Kyle Chang, Katie J. Quinn, Heather L. Gustafson, Florence Dalenc, Cyril Foa, Hanifa Ammarguellat, Chantal Bernard-Marty, Brigitte Lucas, Sophie Barthier, Fabrice Lorchel, Olivier Gisserot, Laurent Arnould, Marjorie Mauduit, Jérôme Lemonnier, Frédérique Berger, Suzette Delaloge, Fabrice Andre. ctDNA Molecular Response based on breast cancer driver mutations predicts progression in aromatase inhibitor-sensitive first line treatment of oestrogen receptor-positive (ER+) HER2-negative (HER2-) advanced breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD17-02.